WO2017157213A1 - Préparation de conjugués formés du docétaxel et d'une substance simplifiée de muramyldipeptide, et effets anti-tumoraux - Google Patents

Préparation de conjugués formés du docétaxel et d'une substance simplifiée de muramyldipeptide, et effets anti-tumoraux Download PDF

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WO2017157213A1
WO2017157213A1 PCT/CN2017/076080 CN2017076080W WO2017157213A1 WO 2017157213 A1 WO2017157213 A1 WO 2017157213A1 CN 2017076080 W CN2017076080 W CN 2017076080W WO 2017157213 A1 WO2017157213 A1 WO 2017157213A1
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cancer
pharmaceutically acceptable
acceptable salt
tumor
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PCT/CN2017/076080
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Chinese (zh)
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刘刚
李硕
温晓明
郑朴荣
张倩立
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深圳信立泰药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides

Definitions

  • the invention mainly relates to a co-supplement formed by the docetaxel and muramyl dipeptide simplification and a synthesis method thereof, and an application thereof in the treatment of cancer, and belongs to the technical field of medicine.
  • Tumor metastasis is one of the essential characteristics of malignant tumors, and it is also the most fundamental cause of cancer treatment failure. More than 80% of clinical cancer patients die from malignant tumor metastasis, and treat tumor metastasis. It is an important way to reduce the mortality of cancer. Controlling metastasis is a key factor determining the prognosis of cancer patients. It has attracted worldwide attention. Tumor metastasis is not only a part of the complex pathogenesis of tumors, but also a treatment that clinical medical workers hope to solve. It is a difficult problem, so it is especially urgent and crucial to seek drugs that inhibit tumor metastasis.
  • Taxanes including paclitaxel and docetaxel, have the characteristics of low oral bioavailability, mainly because they are easily pumped out by the P-glycoprotein of the gastrointestinal epithelium and are easily metabolized by cytochrome P450. Poor water solubility. Since taxanes are still the first-line drugs in their therapeutic field, various studies surrounding such compounds are hot topics for drug chemists. Since the chemical co-suppression of natural anti-tumor drugs and immunopotentiators has been proposed, it is hoped that the combination of chemotherapy and immunotherapy will find new progress in the search for drug molecules with anti-tumor metastasis.
  • the other type is the MTC/MDC series co-insertion formed by linking paclitaxel/docetaxel with muramyl dipeptide derivatives (see WO2011147330A1), and the MTC/MDC series co-insertion inhibits tumor metastasis and inhibits tumor metastasis in vitro.
  • the performance in the middle must have a corresponding effect, but due to its drug-forming problems, further drug use is subject to certain restrictions.
  • the technical problem to be solved by the present invention is to provide a compound with good drug resistance against tumor and tumor metastasis to meet the needs of clinical application.
  • Another technical problem to be solved by the present invention is to provide a process for the preparation of such a compound.
  • Still another technical problem to be solved by the present invention is to provide the use of such a compound for the preparation of a medicament for antitumor and tumor metastasis inhibition.
  • R 1 is selected from a substituted or unsubstituted five- to ten-membered aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted methylene group;
  • the substituted substituent is selected from the group consisting of a hydroxyl group, a thiol group, a halogen group, and an amino group.
  • R 2 is selected from hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and the substituted substituent is selected from a halogen;
  • the aryl group is preferably a 5- to 10-membered aryl group
  • the heteroaryl group is preferably a 5- to 10-membered heteroaryl group.
  • the five-tenth aryl group preferably from a five-membered aryl group, a six-membered aryl group, a ten-membered fused ring aryl group;
  • the five-membered aryl group is selected from
  • the six-membered aryl group is selected from
  • the ten-membered fused ring aryl group is selected from
  • the heteroaryl group means an aromatic ring system of one or more heteroatoms, preferably a heteroaryl group containing from 1 to 4 heteroatoms, preferably from a hetero atom containing N, O or S;
  • Preferred heteroaryl groups are selected from five- to ten-membered heteroaryl groups containing from 1 to 4 heteroatoms selected from N, O or S;
  • the heteroaryl group is selected from a five-membered heterocyclic group containing from 1 to 4 hetero atoms selected from N, O or S, and a six-membered heterocyclic group containing from 1 to 4 hetero atoms selected from N, O or S.
  • the five-membered heterocyclic group containing from 1 to 4 hetero atoms selected from N, O or S is selected from the group consisting of:
  • the six-membered heterocyclic group containing from 1 to 4 hetero atoms selected from N, O or S is selected from the group consisting of:
  • the ten-membered fused heterocyclic group containing from 1 to 4 hetero atoms selected from N, O or S is selected from the group consisting of:
  • the C1-C6 alkyl group in the present invention means a straight-chain or branched alkane group having 1 to 6 carbon atoms, which may be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropane.
  • Base n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, dimethylpropyl, 2-methylbutyl, 2 , 2-dimethylbutyl, 2,3-dimethylbutyl.
  • the C1-C6 alkoxy group is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and Pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, methoxyethoxy, ethoxymethoxy, propoxymethoxy and propoxyethoxy.
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine or iodine
  • the C1-C4 amide group is selected from the group consisting of acetylamino, propionylamino, butyrylamino or isobutyrylamino
  • the C2-C6 alkene group is selected from the group consisting of vinyl And propylene, butenyl, isobutenyl, 2-butenyl, pentenyl, isopentenyl, 2-pentenyl, hexenyl and isohexenyl.
  • the R 2 is hydrogen or hydrogen is replaced by a metal or non-metal cation to form a pharmaceutically acceptable salt selected from the group consisting of Na + , K + , Ca 2+ , Mg 2+ , Zn 2 + , Al 3+ , NH 4 + .
  • the compounds of formula I include, but are not limited to, the compounds of formula IA:
  • R 1 is as defined above.
  • the compound is selected from the group consisting of:
  • the present invention provides a general method for the synthesis of co-adjuvants of docetaxel and muramyl dipeptide simplifications as follows:
  • Reaction reagents and conditions succinic anhydride, TEA, THF, 0 ° C-rt, 4h
  • the concentrate was slowly added dropwise to 10 volumes of ice water to crystallize, and the solid was collected by filtration under reduced pressure; the obtained solid was beaten in ice water, filtered, washed three times with water, and dried at 30 ° C under vacuum. The desired product was obtained as a white solid.
  • the method utilizes various hydroxy resins, such as king resin (loading 0.83mmol/g) as a solid phase carrier, and introduces Fmoc-L-Lys(Boc)-COOH and Fmoc-D- into the resin through the solid phase synthesis strategy of the polypeptide.
  • king resin loading 0.83mmol/g
  • Fmoc-L-Lys(Boc)-COOH and Fmoc-D- into the resin through the solid phase synthesis strategy of the polypeptide.
  • iso-Gln-COOH, Fmoc-L-Ala-COOH and various organic carboxylic acids After completion of the condensation reaction, various steps of the muramyl dipeptide simplification are obtained by sufficiently washing the resin, removing the Fmoc protecting group, and cracking the resin.
  • the various acylation processes in the reaction are conventional amide condensation reactions, by adding an excess of reagents (amino acids or organic carboxylic acids) and potent condensing agents (such as DIC, DCC, HATU, HBTU, BOP, PyBOP, etc.) The condensation reaction is complete.
  • reagents amino acids or organic carboxylic acids
  • potent condensing agents such as DIC, DCC, HATU, HBTU, BOP, PyBOP, etc.
  • Reaction reagents and conditions (a) Fmoc-Lys(Boc)-OH, HOBt, DMAP, DIC, DCM, rt, 12h; (b) Ac 2 O, pyridine, DMAP, DCM, rt, 3h; (c) 20 %piperidine/DMF; rt, 1h; (d) Fmoc-D-iso-Gln-OH, HOBt, DIC, DMF rt, 12h; (e) Fmoc-Ala-OH, HOBt, DIC, DMF, rt, 8h; (f) RCOOH, HOBt, DIC, DMF, rt, 8h; (g) 90% TFA/H 2 O, rt, 2h.
  • Reagents and conditions (a) HOSu, EDC ⁇ HCl, DMSO, rt, 12 h; (b) NMM, DMSO, rt, 12 h.
  • the muramyl dipeptide oligopeptide (1.0 eq.) was added to another reactor, DMSO was added, stirred at room temperature until dissolved, then N-methylmorphine (5.0 eq.) was added, and stirred at room temperature for 5 min, then The reaction solution of the above prepared N-hydroxysuccinimide active ester was slowly added dropwise to the reaction system, and reacted at room temperature for 12 hours.
  • the HPLC monitoring showed that the purity of the N-hydroxysuccinimide active ester intermediate was less than 5 % is considered complete.
  • the reaction system was cooled to 0-4 ° C, and N-methylmorphine in the reaction system was first neutralized with a 1 M aqueous hydrochloric acid solution, and the pH of the reaction system was adjusted to 3 to 5 with a 0.1 M aqueous hydrochloric acid solution. Then, the neutralized reaction solution was slowly added dropwise to 10 volumes of 0-4 ° C ice water to crystallize; the target crude product was obtained by filtration under reduced pressure; the crude product was washed three times with ice water and dried under vacuum at 30 ° C to obtain Target crude. The crude product was purified by HPLC to obtain a co-supplement of the target docetaxel and muramyl dipeptide simplification.
  • the alkane dianhydride of the present invention is selected from the group consisting of C4-C12 alkane dianhydrides.
  • the preparation method of the co-supplement in the invention is mild, the reaction time is short, and the yield is stable, which is advantageous for the synthesis of the compound library by using, for example, a combinatorial chemistry method, and the method for synthesizing the compound library by the combined chemical method also belongs to the invention.
  • each abbreviation is defined as follows, and each reagent can be obtained by commercial means:
  • Another object of the present invention is to relate to the use of the co-inclusion in the treatment or prevention of various tumors, as well as drugs (drugs) or prophylaxis of various cancers caused thereby.
  • the tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, preferably non-small cell lung cancer, breast cancer, breast cancer metastasis, renal cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, Prostate cancer, colon cancer, colon cancer metastasis, brain cancer, preferably brain cancer caused by glioma.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the co-inclusion compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the carrier includes, but is not limited to, various excipients suitable for pharmaceutical preparations, which can be administered to a mammal, particularly a cancer patient, by the gastrointestinal or parenteral route.
  • gastrointestinal administration includes various fillers such as microcrystalline cellulose and the like which can be used as tablets or granules.
  • the compound of the present invention has significantly better solubility and hydrophilicity, and can greatly reduce or avoid the use of the dissolution aid in the research of pharmaceutical preparations, and has significantly better drug-forming properties and drug anti-allergic properties.
  • the compound of the present invention has a good curative effect on a disease caused by abnormal expression of a gene, such as a tumor.
  • the compound of the present invention has an excellent function of inhibiting tumor metastasis while inhibiting tumor.
  • Figure 1 is a comparison of the SST, MDC-405 and docetaxel mouse breast cancer 4T1 lung metastasis model test, in which 1A is the weight comparison result of breast tumor, and 1B is the comparison result of lung surface metastasis nodules, wherein 10 mg S-01 and 10 mg MDC-405 are equimolar with 5.7 mg docetaxel.
  • Figure 2 is a comparison of the results of the 4T1 lung metastasis model of breast cancer in the patents S-01, docetaxel, docetaxel + MDA-1 and docetaxel + MDA-1-linker mice, wherein 2A is the weight comparison of breast tumors.
  • 2B is a comparison of the number of lung surface metastatic nodules, in which 10 mg of S-01 and 5.7 mg of docetaxel were equimolar.
  • Figure 3 Inhibition of human breast cancer MDA-MB-231 xenograft xenografts by S-01, docetaxel, docetaxel + MDA-1 and docetaxel + MDA-1-linker, wherein 3A is As a result of tumor volume comparison, 3B is a tumor weight comparison result, in which DTX represents docetaxel, and 5 mg S-01 and 2.85 mg docetaxel are equimolar.
  • Reaction reagents and conditions (a) SOCl 2 , MeOH, 0 ° C-rt, 12 h; (b) HOSu, EDC.HCl, DMSO, rt, 12h; (c) NMM, DMSO, rt, 12h.
  • the compound S-01 disclosed in the present invention and the MDC-405 reported in the literature are operated according to the pharmacopoeia solubility standard, and the test results show that as the pH value of the buffer increases, the solubility gradually increases, and when the pH value is 6.5 or more, S The solubility of -01 reaches the dissolution level, exhibits better hydrophilicity, and thus exhibits markedly superior drug-forming properties. See Table 1 for the test results.
  • Soluble 1g solute is dissolved in 1 ⁇ 10ml solvent
  • NCI-H460 human large cell lung cancer cells
  • A549 human non-small cell lung cancer cells
  • TCA Trichloroacetic acid
  • DIMETHYL SULPHOXIDE D2438, Lot RNBD1974, Exp: 04/2017
  • the cell-containing cryopreservation solution was transferred to a centrifuge tube of 2, 1000 rpm / min, centrifuged for 5 min;
  • Tris base 0.1211 g of trishydroxymethylaminomethane was accurately weighed and made up to 100 ml by adding ddH 2 O.
  • TCA (50%) (ddH 2 O): Weigh accurately 50 g of TCA, and add ddH 2 O to a volume of 100 ml.
  • H460 cells or A549 were cultured in RPMI-1640 medium containing 10% FBS and 1% penicillin-streptomycin.
  • the logarithmic growth phase cells were resuspended in 5%-1640 complete medium, the cell density was adjusted to 7.5*10 4 cells/mL, 100 ⁇ L/well, seeded in 96-well plates, and the culture plates were placed in an incubator. 24h.
  • the 20 mM stock solution was diluted ten times to obtain a 2*10 -3 M dilution.
  • the dilution was 2*10 -4 M, 2*10 -5 M, 2*10 -6 M, 2*10 - 7 M, 2*10 -8 M, 2*10 -9 M dilution, protected from light, stored at 4 ° C
  • Vehicle control group Take 4 ⁇ L of DMSO, add 796 ⁇ L of 5%-1640 medium, 100 ⁇ L/well/plate
  • Test group Take 2 ⁇ L of each concentration solution and add 398 ⁇ L of 5%-1640 complete medium to obtain 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 100 ⁇ L/well/plate, cultured for 48 h in an incubator at 37 ° C, 5% CO 2 , 100% relative humidity
  • the OD value of the parallel control group was recorded as Tz
  • the OD value of the vehicle control group was recorded as C
  • the OD value of the test administration group was recorded as Ti:
  • the curve was fitted with the software GraphPad and the GI50 was calculated.
  • E means ⁇ 10 n , for example, 5.06E-08 means 5.06 ⁇ 10 -8 .
  • Example 23 using a mouse breast cancer 4T1 lung metastasis model:
  • 4T1 cells were cultured in 1640 medium (Gibco) containing 10% fetal calf serum (Hyclone Corp, USA), 1% glutamine and 1% cyan-streptomycin. 4T1 cells in the logarithmic growth phase were collected and the cell concentration was adjusted to 1.5 ⁇ 10 6 /mL.
  • Female BALB/c mice were inoculated into 4T1 cells in the 4th mammary fat pad, and the inoculation volume was 0.1 mL, that is, 1.5 ⁇ 10 5 /piece.
  • mice 10 animals per group. Mice were administered once a week in the tail vein for 4 consecutive weeks. Animal weight and tumor volume were monitored during the administration. The body weight of the animal was weighed every 2-3 days, and the vernier caliper measures the long and short diameters of the breast tumor, and the tumor size was calculated by the formula: (1/2) ⁇ long diameter ⁇ (short diameter) 2 . On the 28th day after the tumor was received (D28), the experiment was performed. After the blood was collected from the eyeball, the mice were sacrificed by cervical dislocation. The breast tumor was weighed and the lung weight was counted. The number of metastatic nodules on the lung surface was counted. The tumor weight test results are shown in Fig. 1A, and the experimental results of the number of lung surface metastasis nodules are shown in Fig. 1B.
  • S-01, MDC-405, and docetaxel significantly inhibited breast tumor weight and number of pulmonary surface metastasis nodules relative to the blank control group, and more importantly, S-01 vs. positive control
  • the inhibition of docetaxel in the group was significantly different, while the inhibition of MDC-405 was not significantly different from that of docetaxel. It can be seen that S-01 has better tumor suppressor and cancer than MDC-405 and docetaxel. Transfer effect.
  • 4T1 cells were cultured in 1640 medium (Gibco) containing 10% fetal calf serum (Hyclone Corp, USA), 1% glutamine and 1% cyan-streptomycin. 4T1 cells in the logarithmic growth phase were collected and the cell concentration was adjusted to 1.5 ⁇ 10 6 /mL.
  • Female BALB/c mice were inoculated into 4T1 cells in the 4th mammary fat pad, and the inoculation volume was 0.1 mL, that is, 1.5 ⁇ 10 5 /piece.
  • mice 10 animals per group. Mice were administered once a week in the tail vein for 4 consecutive weeks. Animal body weight and tumor volume were monitored during the administration. The body weight of the animal was weighed every 2-3 days, and the vernier caliper measures the long and short diameters of the breast tumor, and the tumor size was calculated by the formula: (1/2) ⁇ long diameter ⁇ (short diameter) 2 . On the 28th day after the tumor was received (D28), the experiment was performed. After the blood was collected from the eyeball, the mice were sacrificed by cervical dislocation. The breast tumor was weighed and the lung weight was counted. The number of metastatic nodules on the lung surface was counted. The results of the tumor weight experiment are shown in Fig. 2A, and the experimental results of the number of lung surface metastasis nodules are shown in Fig. 2B.
  • S-01, docetaxel, docetaxel + MDA-1, and docetaxel + MDA-1-linker significantly inhibited breast tumor weight increase relative to the blank control group, and more importantly, S -01 was significantly different from the positive control group with docetaxel, docetaxel + MDA-1 and docetaxel + MDA-1-linker, indicating that S-01 has better inhibition than the positive control group. Tumor effect.
  • S-01, docetaxel, docetaxel + MDA-1, and docetaxel + MDA-1-linker significantly inhibited the increase in the number of pulmonary surface metastases relative to the blank control group, and more importantly Yes, the inhibition of S-01 was significantly different from that of the positive control group, and the inhibitory effect of docetaxel + MDA-1 and docetaxel + MDA-1-linker increased by 27.9% and 18.6%, respectively.
  • S-01 has a better inhibitory effect on cancer metastasis than the positive control group.
  • mice were raised in SPF Animal Laboratory of Innovative Drug Research Center of Shenzhen Xinlitai Pharmaceutical Co., Ltd.
  • the tumor strain used in the experiment was presented by Professor Liu Gang of the Chinese Academy of Medical Sciences.
  • the tumor strain was MDA-MB-231 breast cancer, the third generation after resuscitation in this laboratory.
  • Grouping and administration tumor-bearing animals with good tumor growth and good general condition were selected, and cervical vertebrae were killed by dislocation. The tumor pieces were taken out under aseptic conditions, and the tumor pieces were cut into 2-3 mm diameter pieces with a scalpel, and the trocars were inoculated subcutaneously in the nude mice. The tumors grew naturally, and were randomly grouped after the tumor volume was as long as 100 mm 3 . Let the group administration date be D0.
  • the tumor length, short diameter and body weight of the animals were measured every 2-3 days during the administration.
  • the tumor volume was calculated by the formula: (1/2) ⁇ long diameter ⁇ (short diameter) 2 , and the experiment was terminated on the 18th day after grouping (D18). .
  • the cervical spine of the animal was dislocated and the tumor was removed, and the tumor weight was measured.
  • the inhibition rate of the drug on the tumor growth was calculated.
  • Tumor volume (TV) and relative tumor volume (RTV) were calculated. The statistical significance of the differences in tumor weight, tumor volume, RTV and other indicators between the groups was compared by t test.
  • Tumor volume (TV) (length x width 2 )/2.
  • Relative tumor volume (RTV) Vt / Vo
  • the evaluation index of antitumor activity is relative tumor growth rate T/C (%),
  • Fig. 3A The results of the tumor volume experiment are shown in Fig. 3A, and the results of the tumor weight experiment are shown in Fig. 3B.
  • S-01, docetaxel, docetaxel + MDA-1, and docetaxel + MDA-1-linker significantly inhibited tumor volume and tumor weight, which is more important than the blank control group.
  • the inhibition of S-01 was significantly different from the positive control group of docetaxel, docetaxel + MDA-1 and docetaxel + MDA-1-linker, indicating that S-01 has a positive relative to the positive control group. Better inhibition of tumors.

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Abstract

La présente invention concerne un composé de formule (I), une préparation de synthèse chimique de conjugués à double fonction capables d'inhiber les tumeurs, les métastases tumorales et les effets de résistance tumorale. Dans la présente invention, de multiples conjugués formés du docétaxel et d'une substance simplifiée de muramyldipeptide sont synthétisés, et des données physicochimiques et des expériences pharmacodynamiques montrent que lesdits conjugués ont une bonne pharmacopotentialité et présentent une plus grande résistance aux tumeurs et aux métastases tumorales.
PCT/CN2017/076080 2016-03-16 2017-03-09 Préparation de conjugués formés du docétaxel et d'une substance simplifiée de muramyldipeptide, et effets anti-tumoraux WO2017157213A1 (fr)

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CN201610148973.9 2016-03-16

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1712399A (zh) * 2004-06-24 2005-12-28 中国医学科学院药物研究所 紫杉醇和免疫增强剂胞壁酰二肽共轭物的制备及用途
WO2011147330A1 (fr) * 2010-05-27 2011-12-01 中国医学科学院药物研究所 Synthèse chimique et effets antitumoraux et antimétastatiques d'un conjugué fonctionnel double

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1712399A (zh) * 2004-06-24 2005-12-28 中国医学科学院药物研究所 紫杉醇和免疫增强剂胞壁酰二肽共轭物的制备及用途
WO2011147330A1 (fr) * 2010-05-27 2011-12-01 中国医学科学院药物研究所 Synthèse chimique et effets antitumoraux et antimétastatiques d'un conjugué fonctionnel double

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU, GANG: "Chemical Biology Study for Anti-Cancer Drug Taxol and Immunostimulant Muramyl Dipeptide Conjugate", MEDICINE & PUBLIC HEALTH, CHINA DOCTORAL DISSERTATIONS FULL-TEXT DATABASE, 15 November 2006 (2006-11-15), ISSN: 1671-6779 *

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